Clearance

Question 1

What are the units for clearance?

Answer 1

Volume/time

Question 2

Is clearance a constant? How do you know?

Answer 2

• Yes

- Because the formula involves K and Vd which are both constants

Question 3

What is the formula for clearance using the compartment model?

Answer 3

Cl = K*Vd

Question 4

Will each drug have their own characteristic clearance rate?

Answer 4

Yes

Question 5

Which parts of ADME are involved in clearance?

Answer 5

Metabolism and excretion

Question 6

What is the formula for clearance using the physiologic model?

Answer 6

Cl = Q*ER

• Q = blood flow
• ER = extraction ratio

Question 7

What is the formula for clearance following model independent?

Answer 7

Cl = Do/AUC

Question 8

What is the formula for ER (extraction ratio)?

Answer 8

(Ca-Cv) / Ca

Question 9

What is the equation for renal clearance?

Answer 9

Clr = (Qu*Cu) / Cp

• Qu = rate of urine flow
• Cu = [drug] in urine

Question 10

What can be concluded from the value of the clearance ratio? What is drug clearance compared to?

Answer 10

• Clearance ratio = drug clearance / inulin clearance
• Less than 1 = partially reabsorbed
• Equal to 1 = filtered only
• Greater than 1 = actively secreted

Question 11

How can you determine renal clearance from a graph of dDu/dt (y axis) against Cp (x axis)?

Answer 11

Renal clearance will be the slope

Question 12

What can be determined based on the slope of a plot on a graph of excretion rate (y axis) vs. Cp (x axis)?

Answer 12

• Perfectly linear slope (slope = 1) = filtration only (diffusion via concentration gradient; no protein)
• Slope greater than 1 = total excretion (transport protein present and filtration occurring at end)
• Slope less than 1 = active secretion (transport protein present, no filtration)

Question 13

How can you calculate fraction of drug excreted (fe)? How can you calculate Clr from fe?

Answer 13

• fe = Du infinity / F*Do

- Clr = fe*Clt (total clearance)

Question 14

What is the formula for clearance after IV infusion?

Answer 14

Cl = R / Css

• R = infusion rate
• Css = [drug] at steady state

Question 15

How can you calculate t1/2 from Cl?

Answer 15

t1/2 = (0.693*Vd) / Cl

Question 16

What affects hepatic clearance?

Answer 16

• Blood flow
• Intrinsic clearance
• Protein binding

Question 17

What is the formula for hepatic clearance (Clh)?

Answer 17

Clh = [Q * (Ca-Cv)] / Ca = Q*ER

same as clearance using the physiologic model

Question 18

What is Cl int? What is it used to describe?

Answer 18

• Intrinsic clearance
• Used to describe ability of the liver to remove drug in the absence of any flow limitation
• Reflects the inherent activity of the mixed-function oxidases

Question 19

What extraction ratio makes a drug be considered highly extracted? What affects their clearance?

Answer 19

• Extraction ratio greater than 0.7 (70% extracted by the organ)
• This means the liver removes the drug almost as fast as its delivered to it
• Increase in blood flow will increase the hepatic clearance rate, so decrease in blood flow will decrease clearance rate
• These drugs are called blood flow limited/sensitive

Question 20

What is important to note about drugs that affect cardiac output?

Answer 20

They will decrease organ blood flow, so will decrease their own clearance rate

Question 21

What extraction ratio makes a drug be considered poorly extracted? What affects their clearance?

Answer 21

• Extraction ratio = 0.1-0.4
• These drugs are enzyme limited
• Hepatic clearance will increase if you induce the enzymes responsible for metabolizing the drugs; if you block these enzymes, hepatic clearance will decrease
• Same will occur if the drug is poorly extracted and eliminated via biliary excretion and you induce that component

Question 22

What causes the majority of variability in half lives or clearance rates?

Answer 22

Drugs that are poorly extracted b/c px have different titers of hepatic enzymes

Question 23

What is the effect on hepatic clearance if Q (blood flow) > intrinsic clearance?

Answer 23

Hepatic clearance = fu*Cl int (fraction unbound * intrinsic clearance; enzyme limited))

Question 24

What is the effect on hepatic clearance if Q (blood flow) < intrinsic clearance?

Answer 24

Hepatic clearance = Q (blood flow limited)

Question 25

What effect on clearance will induction of enzymes have on highly extracted drugs?

Answer 25

Little to no effect on clearance

Question 26

What will be the effect on extraction ratio and clearance of a poorly extracted drug if blood flow is decreased?

Answer 26

• Will decrease the transit time for the drug in the organ, so the drug will have a greater chance of interacting w/ a protein, so extraction ratio will increase
• Clearance won’t change dramatically

Question 27

What will be the effect on extraction ratio of a highly extracted drug if blood flow is decreased?

Answer 27

Will also increase b/c of transit time

Question 28

What does it mean when a drug is considered “capacity limited, binding insensitive”?

Answer 28

• Has a low extraction ratio and low binding to plasma proteins
• Small changes in protein binding won’t product any significant changes in hepatic clearance

Question 29

What does it mean when a drug is considered “capacity limited, binding sensitive”?

Answer 29

• Has a low extraction ratio and high binding to plasma proteins
• Small displacement in protein binding of these drugs will cause a very large increase in free drug concentration, so require special care